Anal cancer is primarily caused by oncogenic human papillomavirus (HPV) types. Persistence of oncogenic HPV infection is the most important early biological event that marks increased risk for development of precancerous anal intraepithelial neoplasia. Annual anal cancer incidence among HIV-negative men having sex with men (MSM) in the US is several fold higher than cervical cancer incidence among women. It is unknown why only some MSM have persistent anal HPV infection and thus increased risk for anal cancer. Such data are especially critical now for two reasons: 1) current HPV vaccines have not been recommended for boys and men, and 2) current vaccines are not licensed for use among men older than 26 years of age. Thus, a fuller understanding of persistent anal HPV infection, is important for the development of anal cancer interventions among MSM. The Moffitt Cancer Center is uniquely positioned for this research as a result of its collection and archiving of anal canal specimens in the Human Papillomavirus in Men Study (HIM Study: NIH R01 CA098803 01), a longitudinal study investigating penile and scrotal HPV infections in men, ages 18-70 years. The HIM Study recruited men in Brazil, Mexico, and the United States beginning in 2005 and also added a post-award protocol to collect anal canal exfoliated cell specimens (anal canal specimen collection and testing was not funded by R01 CA098803 01). The proposed 2-year natural history study will analyze archived biological specimens and behavioral data from 950 men. The men included comprise two groups: all MSM with archived anal specimens (n=357) and a random sample of MSW with archived anal specimens (n=593). We hypothesize that anal HPV infection persistence in MSM is more common than in MSW and is associated with cigarette smoking among MSM. To test the hypothesis, we designed two Specific Aims: 1. Estimate persistence of type-specific anal HPV among MSM and MSW over a 24 month period; and 2. Determine factors independently associated with persistence of anal HPV including age, sexual behavior, cigarette smoking, concurrent sexually transmitted infections, and HPV antibodies. Given the infrastructure and sample size available with the HIM Study, the proposed research is powered to produce findings on HPV persistence that address fundamental questions related to anal cancer. Our proposed research will produce the first robust estimates of anal HPV persistence in MSM and MSW recruited cross-nationally from the general community.